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Emerging mechanistic targets in lung injury induced by combustion-generated particles.
Fariss, M., I. Gilmour, C. Reilly, W. Liedtke, AND A. Ghio. Emerging mechanistic targets in lung injury induced by combustion-generated particles. TOXICOLOGICAL SCIENCES. Society of Toxicology, 132(2):253-67, (2013).
ABSTRACT The mechanism for biological effect following pulmonary exposure to combustion-generated particles is incompletely defined. Transient receptor potential (TRP) cation channels were identified as “particle sensors” in that their activation was coupled with the initiation of 1) protective responses limiting deposition in the airways and 2) inflammatory responses which promote degradation and clearance of the same foreign substances. TRP-A1, -V1, -V4, and -M8 have a capacity to mediate adverse effects after exposure to particulate matter (PM); relative contributions of each depend upon the particle source and composition, dose and deposition, and the expression and function of TRPs in a specific region. Exposure of human bronchial epithelial cells to an organic extract of diesel exhaust particle was followed by TRPV4 mediating an influx of Ca++, increased RAS expression, mitogen-activated protein kinase signaling, and matrix metalloproteinase-1 activation. In addition to TRPs and calcium biochemistry, humic acid (also called humic-like substances; HLS) and iron homeostasis were identified as potential mechanistic targets in lung injury after both wood and cigarette smoke particle exposure. In respiratory epithelial cells, iron sequestration by HLS in wood smoke particle (WSP) was associated with oxidant generation, cell signaling, transcription factor activation, and release of inflammatory mediators. Similar to WSP, insoluble nano-sized spherical particles composed of HLS were isolated from cigarette smoke condensate. These novel pathways of biological effect by combustion-generated particles can be targeted by inhalation of compounds that specifically inhibit critical signaling reactions.
This article summarizes a recent symposium held by the Society of Toxicology on the mechanisms of toxicity by particles.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
ENVIRONMENTAL PUBLIC HEALTH DIVISION
CLINICAL RESEARCH BRANCH